Aston Brain Health Cohort Study (ABaHCoS): Detection of dementia risk to support independent living

The Aston Brain Health Cohort Study (ABaHCoS) will provide fundamental research underpinning a novel suite of easy-to-access tests that together estimate an individual’s brain health and dementia risk.

Dementia has a major impact on healthy life expectancy, and lifestyle changes [1] and emerging treatments (e.g., donanemab [2] and lecanemab [3] for Alzheimer’s disease) are most effective when applied early.

Further, pathological changes, including neurovascular changes [4], neuronal death [5] and the accumulation of Tau and beta-amyloid [6], occur before overt symptoms such as memory loss manifest. Early identification of at-risk individuals is therefore critical for effective disease management.

When combined with emerging treatments and ongoing monitoring, our brain health tests will enable at-risk individuals to adopt beneficial lifestyle changes, engage in life-planning, access timely treatment, and maintain their independence for longer.

This proof-of-concept study will thus address the strategic priority of “Preventing, delaying or reducing future health and social care requirements, in particular, improving the ability to maintain functional independence for older adults”. Our emphasis on early prediction makes easy access to tests critical to the impact of the project.

Figure 1 illustrates possible pathways into our tests and how individual outcomes might be managed.

Natural changes in the eye generally lead to eye tests from the age of 40 onwards, presenting an ideal opportunity to assess brain health. Others may access the tests via regular health screening.

For individuals not attending such clinics, carefully calibrated tests administered online may prompt self-referral to GPs or pharmacies.

We envisage that blood tests will reinforce the initial non-invasive testing with follow-up testing to track neurobiological changes and help time interventions.

Building on ARCHA’s multidisciplinary capacity we will set up a unique Doctoral Training Programme in which our PGRs will develop tests for brain age / health operating at multiple levels from molecules to minds: Figure 2.

We propose a novel battery of tests to assess changes in cell function, neurovascular structure, neurophysiology, perception, and cognition.

Working individually, PGRs will characterise how specific tests measure brain health comparing typical and atypical ageing and cross-correlating multiple measures of brain function.

Working together our PGRs will correlate these tests with chronological age in a cohort of typically ageing people (the ABaHCoS cohort) assessed for possible confounding factors such as years in education, socio-economic status, and general health. We will develop a mathematical model for combining test results to produce accurate estimates of brain age.

When an individual’s brain age exceeds their chronological age (or increases faster than normal), this will be an indication of poor brain health and dementia risk. We will also explore, cognitive tasks, MR imaging (MRI) and liquid biopsies as potential monitoring tests.

Figure 2 shows how our experiments will be grouped into four interlocking themes and illustrates the progression from initial characterisation to brain health tests and ongoing monitoring.

To ensure the study is robust, our PGRs will work as a team: pooling participant recruitment and cross-trained in data collection. Further, any sub-set of tests can provide beneficial predictions.

Critically while the battery of tests proposed is novel in combination, each will build on previous and current projects at Aston: scaffolding the ABaHCoS PGRs.

The four themes are: Cognitive decline: Building on the Cam-CAN [7] and ELSA-HCAP [8] studies which focus on declines in general factors such as fluid intelligence, this theme will explore a range of more implicit cognitive tasks such as navigation [9], and decision reaction time [10], and measures of social cognition such as ‘Theory of Mind’ and emotion recognition tests which correlate with measures of executive function in patients with neurological conditions [11].

These cognitive tests will afford both online self-testing and ongoing monitoring. We will cross corelate these tests with perceptual and neurophysiological measures, linking to our second theme.

Neurophysiology and Perceptual decline: Aiming at tests that can be administered as part of a standard eye test, this theme will explore perceptual tasks such as motion [12] and texture perception [13], which change with age irrespective of ocular decline, correlating these with neural measures and the cognitive tests described above.

This theme will also consider neuroimaging measures of brain activity (EEG and MRI).

Changes in the power spectral density of the EEG [14], including the peak frequency of the alpha oscillation, correlate strongly with age and relate to executive control and neural inhibition. We will thus establish a simple 2-electrode EEG test for brain age.

Similarly, both the brain’s haemodynamic response and the balance of neural inhibition and excitation alter progressively with age and can be detected using MRI [15] providing validation of other measures, and follow-up monitoring. MRI can also detect neurovascular changes linking to our third theme.

Neurovascular ageing: This theme aims to understand the contribution of platelet reactivity [16] and white blood cell bioenergetics to endothelial cell dysfunction [17] and their association with neurovascular changes [18] to: 1) identify changes in the inflammatory response, migration, proliferation, permeability, and mitochondrial function of human brain endothelial cells; 2) identify markers for vascular- and neural-inflammation; 3) correlate such markers with neurovascular changes (observed via MRI [20]) and similar, but more accessible, changes in the retina.

This theme will provide early detection via finger-tip temperature tests for endothelial cell dysfunction, retinal imaging, and blood tests and links via neurovascular changes, endothelial cell function, and inflammation to our final theme.

Cellular communication and cell death: Aiming primarily toward liquid-biopsies for ongoing monitoring, this theme seeks to understand age-related changes in astrocytes [19], the majority cell type in the brain, and other components of the neurovascular unit (e.g. pericytes, neurones, endothelial cells, microglia), and their effect on brain function.

Using in vitro models and human plasma samples we will study how vascular-glial metabolic coupling supports neuronal function changes during ageing by assessing extracellular vesicles distribution, size and composition (proteomic and RNA sequencing), inflammation, oxidative stress and neuronal cell death [21].

The identification of extracellular vesicles resulting from cell death will enable early confirmation of disease onset once risk has been established and thus be critical for timing treatment interventions.